Cellular and viral nucleic acids are potential targets for therapeutic intervention in disease processes. The long range goal of this project is to develop oligonucleotide analogs and derivatives which can interact wit double-stranded nucleic acids in a predictable and sequence-specific manner. The specific aims of the project are: A) Design and synthesized derivatives of uracil and cytosine which can interact with one or more pyrimidine-purine base pairs "imbedded" in a (purine), (pyrimidine), tract of duplex DNA or RNA; B) Study the ability of these oligomers to form triplexes with double-stranded DNA target molecules; C) Synthesize oligo-2'-O-methylribonucleotides which are designed to interact with single-stranded RNA sequences via intramolecular duplex/triplex formation. These oligomers will also be further modified with alkyl imidazole functional groups in an effort to facilitate cleavage of target RNA internucleotide bond; and D) Study the ability of oligomers containing 8-oxoadenine and other base analogs prepared in Specific Aim 1 to inhibit collagenase IV gene expression in transformed human fibrosarcoma (HT1080) cells in culture. Success in these areas could lead to the rational design of therapeutic agents which act by controlling gene expression at the DNA or RNA level.